Epilepsy is one of the most prevalent chronic neurological diseases of childhood, and if left uncontrolled, results in permanent developmental and physical debilitation. Most epileptic seizures are rendered inactive by proper use of anti-epileptic medications, but in 30–40% of patients, such medications are inadequate in controlling the repeated bouts of seizures, and this rate has remained almost constant despite recent development of many novel therapeutic drugs.1,2 Hence, surgical intervention has gained increasing prominence in these patients.

Surgical treatment of refractory epilepsy has been an option for more than 100 years, but recent advances in neuroimaging techniques have greatly increased the efficacy, as well as safety of surgical ablation of refractory epilepsy, and we have experienced exponential growth in epilepsy surgery during the last two decades.2 Certain types of epilepsy are especially prone to good surgical outcome, as to be dubbed “surgically remediable syndromes”. These include the mesial temporal lobe epilepsy, which may be the most common form of such epilepsies, and neocortical epilepsies caused by discrete, readily resectable foci.3,4 When surgical intervention is performed promptly enough in such cases, resulting seizure ablation provides valuable opportunities for epileptic children to catch up on physical and psychological development.5 However, even though results of temporal lobe resections in pediatric temporal lobe epilepsy are excellent, with seizure freedom achieved in up to 63.3% of patients,6 a subset remains where resection of temporal lobe was not effective, although all pre-surgical evaluations pointed to ipsilateral temporal lobe origin of seizures. In some of these patients, seizures originating from the insular cortex are believed to be the reason behind the surgical failures.7,8

The semiology of insular seizure is described as being similar to seizures of temporal or frontal lobe origin.8 Coupled with the fact that surgery of the insular is not a generally accepted treatment option in many institutions due to its proximity to the language cortex, difficulty of surgical approach and abundance of hidden, essential blood vessels,9 proper selection of candidates for insular resection is difficult but paramount for better successes in epilepsy surgery. This selection, however, needs to be done with great caution due to higher risk that insular surgery entails in comparison to temporal lobe surgery.

Long-term intracranial electrocorticographic (EcoG) recording is useful for delineating patients with temporal lobe epilepsy, but it has only limited value in analyzing ictal discharges originating from such deep cortical structures as insula. Stereo-electroencephalopgraphic (SEEG) recording is useful in selecting patients with seizures of insular origin,8 but the invasive nature of this tool forbids its routine application in all temporal lobe epilepsy patients. Hence, we have focused on determining the usefulness of fluorine-18 fluorodeoxyglucose positron emission tomography ([¹⁸F]FDG-PET) studies in selecting patients in need of further invasive insular monitoring through utilization of post-surgical results after temporal lobe surgery, by verifying whether patients with insular hypometabolism present with poorer post-surgical outcome.

Surgical treatment of refractory epilepsy has gained increasing prominence in recent decades. Advancements in non-invasive diagnostic modalities such as higher resolution MRI, PET scans and SISCOM have permitted more accurate localization of epileptic lesions and better pre-operative planning, resulting in improved surgical outcomes with less post-operative morbidities.11 This has resulted in routine performance of anteromesial temporal lobe resections in circumstances when epilepsy remains refractory to multiple AEDs, with high attainment of seizure freedom.12 Kwan and Brodie have observed that even with the introduction of newer AEDs since the early 1990s, the proportion of patients suffering from intractable epilepsy have stayed very much constant. In fact, it is now becoming clear that new AEDs have struck little impact on attaining seizure freedom in patients suffering from drug-resistant epilepsy.1 When these points are taken into consideration, it becomes clear that early surgical intervention is beneficiary, if not critical, in obtaining seizure freedom if more than two appropriate AEDs fail to control the seizures.13

Early seizure freedom is especially vital in pediatric patients, since repeated bouts of seizure attacks can have devastating impact on a child’s neurological development at a time when its loss would be ultimately unrecoverable. However, there exists a small subset of patients in whom temporal lobectomy provided little benefit, even though pre-surgical long-term EEG and imaging modalities such as MRI and PET pointed to the ipsilateral origin of temporal lobe epilepsy.

In early 1950s, Guillaume and Mazars were the first to point out that seizures originating from the insular cortex might be the reason behind these surgical failures, and stated that seizures originating from the insular cortex resembled seizures originating from the temporal lobe to such a degree that confusion on the origin of the epileptic discharge might result in erroneous resection of the brain.14,15 This hypothesis was later repeated by Penfield and Jasper,16 but the impact of insular cortex on the post-surgical outcome remained much debated.

Some later researches by other groups stated that insular involvement in mesiotemporal lobe epilepsies could explain the late persistence of disabling seizures in up to 30% of patients after anterior temporal lobe lobectomy,17–19 and this resulted in a brief surge of anterior temporal lobectomy with associated insulectomy. However, a large-scale analysis of surgical outcome among temporal lobectomy with associated insulectomy was performed from 1941 to 1962 by Silfvenius et al, and the result was compared with matching control group of usual temporal lobectomy.19 Surprisingly, no significant difference in the surgical outcome was observed among these 2 groups, and the insulectomy group presented with a much higher morbidity after the procedure. This led to abandoning of the insulectomy as one of the options for TLE patients in many institutions, and the question of insular involvement in TLE was not investigated further.

Insular surgery regained its spotlight in the 21st century when Isnard and colleagues demonstrated that seizures spreading to the ipsilateral insular cortex correlated with favorable surgical outcome, whereas seizures originating from insular itself did not benefit from conventional temporal lobe surgery.7 This article also pointed out the fact that in aforementioned Silfvenius’ research, higher percentages of patients benefited from insular surgery if it was performed after temporal lobectomy failure as opposed to patients who did not receive follow-through surgery, and suggested in concordance with his research that insular surgery is necessary if seizures originated from the insular cortex itself.

Differentiation of TLE with epilepsy of insular origin is, however, extremely difficult. Symptoms induced by insular stimulation are similar to the symptoms observed during temporal lobe seizures,16,17 and clinical observations of seizures with known insular lesion described its semiology as being similar to temporal7 and frontal20 lobe seizures. This is quite forseeable, since insular lobe and temporo-limbic structures such as olfactory cortex, cingular cortex, entorhinal cortex, amygdala, and hippocampus share dense neural connections with each other. Initial sequential occurence of laryngeal discomfort with thoracic oppression or dyspnea, unpleasant paresthesiae, or warmth sensation focused on the perioral region or extended to a large somatic territory, and dysarthric, dysphonic speech before the onset of somatomotor symptoms raises the possibility that the seizure originated from the insular cortex,8 but selection of candidates for insular cortisectomy based simply on clinical semiology remains too risky.

The most confirmative method would be to record the actual ictal discharges originating from the insula. Wieser employed SEEG recording in TLE patients to verify the route of ictal electrographic propagation and found that epileptic discharges evolving from the temporal lobe takes preferential spread from amygdale and hippocampus towards orbitofrontal cortex, which explained the high rate of hippocampal sclerosis in chronic TLE patients.21 Isnard et al employed the same SEEG technique to verify the route of ictal discharge in insular seizures, and found that discharges from TLE frequently and rapidly spreads to the insular regions by mostly following one of two constant pathways - namely, through hippocampal relay and through external temporal neocortex.7 This propagative pattern makes the differentiation between temporal and insular epilepsies difficult, as use of simple intracranial ECoG alone would not permit the differentiation of seizures of insular origin from primarily temporal lobe seizures. Since patients suffering from secondary insular epilepsy can benefit from simple ATL, and because seizures originating primarily from insular cortex are responsible for surgical failures, it is imperative for clinicians to be able to differentiate TLE patients from insular epilepsy. Simple ECoG does not provide adequate information in this regard. Invasive SEEG monitoring is the only method to confirm seizures originating from the insular cortex, but its invasiveness makes it an unattractive option for routine application.

Imaging analysis is non-invasive, and unlike EEG-based methods, they are not dependent on electrical activity of the brain. They are also performed as part of the routine pre-surgical evaluations in all patients undergoing epilepsy surgery in our institution. [¹⁸F]FDG-PET, in particular, is an important tool in delineating the ictal onset zone and in understanding the neurobiology and functional alterations caused by various forms of epilepsy. The glucose analogue tracer, [¹⁸F]FDG, is and indirect marker of neuronal activity. It allows the quantification of cerebral glucose metabolism, and interictal [¹⁸F] FDG-PET has established its role in non-invasive localization of epileptogenic foci. It also reflects the dynamic seizure-related changes in cerebral cellular functions. Interictal epileptogenic foci tend to appear as zone of hypometabolism on [¹⁸F]FDG-PET. In TLE, comparison of hypometabolism with contralateral side has been shown to be useful for localization of the epileptogenic zone.22 Numerous studies employing large number of patients have reported a sensitivity of 70–85% for [¹⁸F]FDG-PET in TLE.23–25 [¹⁸F]FDG-PET analysis is especially known to be useful in delineating the epileptic zone in MRI-negative, PET-positive TLE.23 Therefore, it can be inferred that this modality would also prove to be useful in detecting lesions proximal to the temporal lobe, such as the insula.

Our analysis, however, shows that the presence of insular hypometabolism in [¹⁸F]FDG-PET does not have any impact on the post-surgical outcome. Patients with insular hypometabolism did not differ significantly with non-hypometabolic group in regard to their clinical characteristics such as onset age, sex, number of AED used, or seizure duration, so this result does not seem to be the result of an obscure and inherent confounding variable residing within the study population. Both patient groups differed significantly only by the age at surgery, with the insular hypometabolic group receiving surgery at an earlier age. This could be considered as being caused by the non-hypometabolic group presenting with less severe symptoms, which caused delay in reaching the decision to take surgery until a later age, although the duration of seizures between the two groups was not significant. In addition to the statistical result, 3 recipients of insular cortisectomy, all of whom showed significant insular hypometabolism in PET images, ultimately presented with poor post-surgical outcomes. This may be caused by the presence of obscure dual pathology or diaschisis in other cortical areas that were not detectable in our pre-surgical evaluations. These 3 patients tended to present with earlier onset of seizures with shorter time interval to surgery, and took more anti-epileptic drugs than the mean value of cohorts, but since the absolute number of the insular cortisectomy was too small to glean any significant patterns, their clinical characteristics seems to be unhelpful until more patients are enrolled. However, their poor response to surgery is supportive of the result of our statistical analysis.

Although the statistical significance was lacking, it is noteworthy to observe that the trend shows a general tendency towards better surgical outcome in patients without insular hypometabolism. Therefore, it may be possible that with a larger number of cohort, the final result might be different. But at present, our result is in concordance with previously published report by Bouilleret et al, who stated that the degree of hypometabolism in the ipsilateral insula by FDG-PET was not related to the post-operative outcome.26 This result is understandable, since the densely interconnected neural network present in the insular cortex allows for rapid spread of ictal discharges, and this leads to an overestimation of the size of the seizure onset zone. Such wide involvement of the epileptic discharges results in wider areas of interictal hypometabolism in FDG-PET, leading to difficulties in pinpointing the area of the origin of ictal discharges. Insular resection has therapeutic meaning in only patients with primary insular epilepsy, so FDG-PET analysis seems to have limited values so far in replacing long-term SEEG in selecting patients suitable for insular surgery, but further studies are needed to verify this point.

Our study is limited in that the sample size was too small to warrant high statistical meaning to its results. The sample size was too small for analysis of certain variables such as MRI and PET results, or post-operative pathological findings. It does, however, show some promising data, such as its tendency towards better surgical outcome among PET negative group, and warrants further study in the near future with employment of a larger cohort. Also, the study can benefit from division of the cohort into more specialized subgroups, such as groups dedicated specifically to insular cortisectomy patients, and analyzing the PET findings in relation to their post-operative outcome. This will provide more precise insight into the role insular hypometabolism plays on the need for insular surgery, but insular cortisectomy is still a rare and carefully applied procedure in our institution-in fact, it is performed very sparingly in almost all institutions the world over-and the absolute size of the sample is still too small for this method. Gradual accumulation of the insular surgery data, however, is on the way, and we expect to be able to perform a more elaborate study in the coming future.